Many lung and prostate cancers, of which small cell lung cancer (SCLC) is a prime example, have a neuroendocrine phenotype, and their growth is stimulated by neuropeptides. Antagonists of several peptides (e.g. bradykinin, substance P, bombesin) have been used in experimental treatment of models of SCLC in animals. Among the most potent of the peptides examined thus far, crosslinked dimers of bradykinin antagonist peptides have been efficacious both in vitro and in vivo against strains of SCLC and other tumors (Chan et al., Immunopharmacology 33: 201-204, 1996; Stewart et al., Can. J. Physiol. Pharmacol. 75: 719-724, 1997; Stewart et al., U.S. Pat. No. 5,849,863). Prostate cancers show a similar neuroendocrine phenotype and are susceptible to these neuropeptide antagonists.
Bradykinin (BK: Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg (SEQ ID NO: 1)) is an important growth factor for many types of cancers. Many cancers express receptors for BK and overproduce BK to stimulate their growth. In addition to direct stimulation of cancer growth, BK stimulates angiogenesis in solid tumors by stimulating release of vascular endothelial growth factor (VEGF) and facilitates tumor spreading and invasion by stimulating release of matrix metalloproteases (MMPs). Thus, antagonists of BK have three potential tumor-inhibiting activities.
The first BK antagonists developed were peptides which did not show any anti-cancer activity. Thereafter, several non-peptide BK antagonists were reported from several laboratories (Inamura et al., Can. J. Physiol. Pharmacol. 75: 622-628, 1997). The present inventors also discovered a group of acylated amino acid amides having BK antagonist activity that are also potent anti-cancer agents (see U.S. Pat. No. 6,388,054). Following the discovery that certain dimerized bradykinin antagonist peptides are cytotoxic for cancer cells and inhibit tumor growth, interest grew in finding smaller, non-peptide BK antagonists with similar anti-cancer efficacy but lower cost of synthesis as well as the possibility non-parenteral routes of administration.